C to T mutations at dipyrimidine sites are the principal mutations induced by sunlight light.  These C to T mutations have been correlated with cis-syn cyclobutane pyrimidine dimers (CPDs) which are more frequently formed at methylated CpG sites.  Methylated CpG sites are also hotspots for C to T mutations in the p53 gene of skin cancers.   CPDs are bypassed primarily by the DNA damage bypass polymerase ?, which synthesizes past the initially formed CPDs in a non-mutagenic manner.  C-containing CPDs are not stable, however, and spontaneously deaminate to U, while mC-containing CPDs deaminate to T.  When polymerase ? synthesizes past a deaminated CPD, an A is inserted opposite where a C or mC was originally, resulting in a C to T mutation.  We will describe our recent investigations on the effect of methylation, sequence context, protein binding, and nucleosome position on CPD formation and deamination in vitro and in vivo and how they may contribute to the origins of UV mutation hotspots and cold spots.

Mechanistic studies of the deamination-bypass pathway for sunlight-induced C to T mutations observed in skin cancers

244th National Meeting (2012)

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